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Predicting in vivo oral absorption of poorly soluble drugs from their in vitro dissolution-precipitation profile in biorelevant media
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2015 (English)Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
Abstract [en]

Introduction: Drug absorption is a complex process involving dissolution and precipitation, along with other kinetic processes. A deep understanding of these processes can support drug development during compound selection, formulation development, clinical study design and regulatory interactions. Aim: The purpose of this work was to 1) establish an in vitro methodology to study dissolution and precipitation in early stages of drug development where low compound consumption and high throughput are necessary, 2) develop a mathematical model for a mechanistic explanation of generated in vitro dissolution and precipitation data and 3) extrapolate in vitro data to in vivo situations using physiologically based models to predict oral drug absorption. Methods: Small-scale dissolution and pH-shift studies were performed in biorelevant media to monitor the precipitation profiles of a set of poorly soluble weak bases. After developing a dissolution-precipitation model from this data, it was integrated into a simplified, physiologically based absorption model to predict oral fraction absorbed of the selected compounds and to simulate the PK profile of a set of clinical studies. Results: The model helped explain the consequences of supersaturation behavior of the weakly basic compounds. The predicted human pharmacokinetic profiles closely aligned with the observed clinical data. Conclusions: A new approach combining experimental dissolution/precipitation methodology with a mechanistic model has been developed for the prediction of human drug absorption kinetics. The approach unifies the dissolution and precipitation theories and enables accurate predictions of in vivo oral absorption by means of physiologically based modeling.

Place, publisher, year, edition, pages
2015. , 40 p.
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-273717OAI: oai:DiVA.org:uu-273717DiVA: diva2:894965
External cooperation
F. Hoffmann-La Roche
Available from: 2016-01-18 Created: 2016-01-17 Last updated: 2016-01-18Bibliographically approved

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